BACKGROUND: There is an ongoing debate as to whether sex could be associated with immune checkpoint inhibitor (ICI) benefit. Existing literature data reveal contradictory results, and data on first-line immune combinations are lacking. METHOD: This was a real-world, multicenter, international, observational study to determine the sex effects on the clinical outcomes in metastatic renal cell carcinoma (mRCC) patients treated with immuno-oncology combinations as first-line therapy. RESULTS: A total of 1827 mRCC patients from 71 cancer centers in 21 countries were included. The median OS was 38.7 months (95% CI 32.7-44.2) in the overall study population: 40.0 months (95% CI 32.7-51.6) in males and 38.7 months (95% CI 26.4-41.0) in females (p = 0.202). The median OS was higher in males vs. females in patients aged 18-49y (36.9 months, 95% CI 29.0-51.6, vs. 24.8 months, 95% CI 16.8-40.4, p = 0.426, with + 19% of 2y-OS rate, 72% vs. 53%, p = 0.006), in the clear cell histology subgroup (44.2 months, 95% CI 35.8-55.7, vs. 38.7 months, 95% CI 26.0-41.0, p = 0.047), and in patients with sarcomatoid differentiation (34.4 months, 95% CI 26.4-59.0, vs. 15.3 months, 95% CI 8.9-41.0, p < 0.001). Sex female was an independent negative prognostic factor in the sarcomatoid population (HR 1.72, 95% CI 1.15 - 2.57, p = 0.008). CONCLUSIONS: Although the female's innate and adaptive immunity has been observed to be more active than the male's, women in the subgroup of clear cell histology, sarcomatoid differentiation, and those under 50 years of age showed shorter OS than males.

Biomedical Center Faculty of Medicine in Pilsen Charles University Alej Svobody 76 Pilsen Czech Republic

Clinical Oncology Sociedad de Oncología Y Hematología del Cesar Valledupar Colombia

Department of Clinical Oncology and Radiotherapy University Hospital Hradec Kralove Hradec Kralove Czechia

Department of Comprehensive Cancer Care and Faculty of Medicine Masaryk Memorial Cancer Institute and Masaryk University Brno Czech Republic

Department of Genitourinary Medical Oncology and Clinical Pharmacology National Institute of Oncology Budapest Hungary

Department of Health Sciences University of Florence Florence Italy

Department of Medical and Surgical Sciences University of Bologna Bologna Italy

Department of Medical Oncology Army Hospital Research and Referral New Delhi India

Department of Medical Oncology MD Anderson Cancer Center Madrid Madrid Spain

Department of Medical Oncology University Hospital Ramón y Cajal Madrid Spain

Department of Medical Surgical Sciences and Biotechnology La Sapienza University Polo Pontino Rome Italy

Department of Medicine and Surgery University of Parma Via Gramsci 14 43126 Parma Italy

Department of Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Oncology and Radiotherapeutics Faculty of Medicine and University Hospital in Pilsen Charles University Alej Svobody 80 Pilsen 304 60 Czech Republic

Department of Precision Medicine in Medical Surgical and Critical Care Section of Medical Oncology University of Palermo 90127 Palermo Italy

Department of Uro Oncology Maria Sklodowska Curie National Research Institute of Oncology Warsaw Poland

Department of Urology Medical University of Innsbruck Innsbruck Austria

Department of Urology University Hospital Bonn 53127 Bonn Germany

Division of Hematology Oncology Department of Medicine Samsung Medical Center Sungkyunkwan University School of Medicine Seoul 06351 Republic of Korea

Division of Oncology Department of Internal Medicine Medical University of Graz 8036 Graz Austria

Hematology and Oncology Department Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán Mexico City Mexico

Latin American Cooperative Oncology Group LACOG Porto Alegre Brazil

Latin American Cooperative Oncology Group LACOG Porto Alegre RS Brazil

Markey Cancer Center University of Kentucky Lexington KY 40536 0293 USA

Medical Oncology IRCCS Azienda Ospedaliero Universitaria Di Bologna Bologna Italy

Medical Oncology Tawam Hospital Al Ain United Arab Emirates

National Cancer Centre Singapore Singapore Republic of Singapore

Niguarda Cancer Center Grande Ospedale Metropolitano Niguarda Milan Italy

Oncology and Hematology Center of Hospital Albert Einstein Hospital Albert Einstein Sao Paulo Brazil

Oncology and Hematology Department Hospital Sírio Libanês Brasilia DF Brazil

Oncology Division Hospital 'Maria SS Dello Splendore' ASL 4 Giulianova Italy

Oncology Unit Macerata Hospital Macerata Italy

Oncology Unit S Maria Delle Grazie Hospital ASL NA2 NORD 80078 Pozzuoli Naples Italy

Oncology Unit University Hospital of Parma Via Gramsci 14 43126 Parma Italy

PUCRS School of Medicine Porto Alegre RS Brazil

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Sex as modifier of survival in patients with advanced urothelial cancer treated with pembrolizumab